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Neurology. 2018 May 22;90(21):e1842-e1848. doi: 10.1212/WNL.0000000000005566. Epub 2018 May 2.

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.

Author information

1
From the Wellcome Centre for Mitochondrial Research (G.S.G.), Institute of Genetic Medicine (B.B., M.J., J.S.M., J.D., H.G., H.L., P.F.C., A.R., R.H.), and Institute of Neuroscience (M.R.B., R.G.W., G.S.G.), Newcastle University, Newcastle upon Tyne, UK; Leibniz-Institute für Analytische Wissenschaften-ISAS-e.V. (V.P., A.R.), Dortmund, Germany; Departments of Neurology (M.R.B., J.A.L.M., G.S.G.) and Clinical Neurophysiology (M.R.B., R.G.W., R.H.), Royal Victoria Infirmary, Newcastle upon Tyne; Department of Cellular and Molecular Physiology (J.O., L.E.S.), Institute of Translational Medicine, University of Liverpool; Department of Clinical Neurosciences (P.F.C.), University of Cambridge, Cambridge Biomedical Campus, UK; Department of Neuropediatrics and Muscle Disorders (H.L.), Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; and Centro Nacional de Análisis Genómico (CNAG-CRG) (H.L.), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
2
From the Wellcome Centre for Mitochondrial Research (G.S.G.), Institute of Genetic Medicine (B.B., M.J., J.S.M., J.D., H.G., H.L., P.F.C., A.R., R.H.), and Institute of Neuroscience (M.R.B., R.G.W., G.S.G.), Newcastle University, Newcastle upon Tyne, UK; Leibniz-Institute für Analytische Wissenschaften-ISAS-e.V. (V.P., A.R.), Dortmund, Germany; Departments of Neurology (M.R.B., J.A.L.M., G.S.G.) and Clinical Neurophysiology (M.R.B., R.G.W., R.H.), Royal Victoria Infirmary, Newcastle upon Tyne; Department of Cellular and Molecular Physiology (J.O., L.E.S.), Institute of Translational Medicine, University of Liverpool; Department of Clinical Neurosciences (P.F.C.), University of Cambridge, Cambridge Biomedical Campus, UK; Department of Neuropediatrics and Muscle Disorders (H.L.), Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; and Centro Nacional de Análisis Genómico (CNAG-CRG) (H.L.), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. Rita.Horvath@ncl.ac.uk.

Abstract

OBJECTIVE:

To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases.

METHODS:

We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts.

RESULTS:

The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice.

CONCLUSION:

We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.

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